TISSUE-SPECIFIC COORDINATE REGULATION OF ENZYMES OF CHOLESTEROL-BIOSYNTHESIS - SCIATIC-NERVE VERSUS LIVER

Exposure of weanling rats to a diet containing the element tellurium r esults in specific inhibition of squalene epoxidase, an obligate enzym e in cholesterol biosynthesis. Liver responds to the resulting intrace llular sterol deficit by up-regulating, in parallel and to the same ex tent, expression of mRNA for squalene epoxidase and for HMG-CoA, reduc tase, the major rate-limiting enzyme in the pathway. This increased mR NA expression, coupled with additional translational and posttranslati onal activation of the pathway, allows normal levels of cholesterol sy nthesis in liver despite tellurium-induced inhibition of squalene epox idase. The response to tellurium challenge in sciatic nerve is very di fferent. In this tissue, cholesterol synthesis is prominent because of the large amount of cholesterol required for synthesis and maintenanc e of myelin. Although nerve shows an initial (at 1 day) up-regulation of mRNA expression for both enzymes in response to tellurium exposure, this is followed quickly by parallel down-regulation of both enzymes, in concert with down-regulation of mRNA expression for myelin protein s. We suggest that the tellurium-induced deficit in sterols leads to a coordinate down-regulation of synthesis of myelin components . The in itial early up-regulation of cholesterol biosynthesis in sciatic nerve due to the cholesterol deficit is countered by down-regulation which is coordinated with overall control of the program of myelin assembly. This tissue-specific control of cholesterol synthesis in sciatic nerv e is a point of vulnerability to toxicants, and may be related to the need for coordinate synthesis of all components of myelin.